Ferroptosis modulation by METTL14 in cancers: From molecular insights to therapeutic strategies.

Ferroptosis is an iron-dependent, lipid peroxidation-driven form of regulated cell death that is mechanistically distinct from apoptosis and necrosis. In cancer, it plays a dual role: it can act as a tumor suppressor mechanism, yet may also contribute to therapy resistance and immune modulation. Methyltransferase-like 14 (METTL14), a key subunit of the N6-methyladenosine (mA) methyltransferase complex, post-transcriptionally regulates gene expression by influencing RNA stability, splicing, and translation. Emerging evidence reveals that METTL14 modulates ferroptosis in a context-dependent manner by targeting core regulators, including Solute Carrier Family 7 Member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4), and ferroptosis suppressor protein 1 (FSP1), through mA modification. This review synthesizes recent progress on the METTL14-ferroptosis axis across multiple cancer types, such as colorectal, esophageal, hepatocellular, non-small cell lung, endometrial, and cervical cancers. We systematically outline the molecular mechanisms through which METTL14 either promotes or inhibits ferroptosis and evaluate its therapeutic relevance. Challenges and future perspectives for targeting this regulatory axis in oncology are also discussed.